IMPACT OF ANGIOTENSIN-CONVERTING ENZYME-SUBSTRATE CONFORMATION ON FRACTIONAL HYDROLYSIS IN LUNG

We examined the hydrolysis kinetics of benzoyl-phenylalanyl-glycyl-pro line (BPGP) in the isolated perfused lung and in vitro for evidence of preferential hydrolysis of the trans isomer by angiotensin-converting enzyme (ACE). Nuclear magnetic resonance spectroscopy showed that BPG P exists as cis and trans isomers in a ratio of 44:56. After a single pass through the perfused rabbit lung over a wide range of infused BPG P concentrations, 42% of the BPGP was not hydrolyzed. In single-pass b olus-injection studies, 41% of the injected BPGP was not hydrolyzed, a nd very little further hydrolysis occurred in a second passage of the bolus through the lungs. In rat lung recirculation and in vitro studie s of BPGP hydrolysis by ACE, similar to 60% of the substrate was hydro lyzed rapidly compared with the remaining similar to 40%, and the pept idyl-prolyl cis-trans isomerase cyclophilin increased the rate of the slower phase of the reaction in both kinds of experiments. We conclude that the rapid hydrolysis phase represents primarily the hydrolysis r ate of the traits isomer and the slower phase the cis-trans isomerizat ion rate, suggesting that the trans isomer of BPGP is preferentially h ydrolyzed by ACE in the perfused lung and in vitro.